The repeated use of psychostimulants and opiates produces adaptations within the CNS that are thought to contribute to persistent and compulsive drug abuse. Our studies have as their goals the delineation of neuroadaptations that occur within the mesocorticolimbic system, a circuit implicated in mediating the behavioral effects of various drugs of abuse, and the identification of homeostatic mechanisms that oppose their development and long-term expression. Included in this goal is the identification of pharmacotherapies that attenuate alterations in behavior and brain chemistry that occur as a consequence of repeated drug use. These studies have demonstrated that dopamine neurotransmission within two brain regions that are components of the mesocorticolimbic systems, the medial prefrontal cortex and nucleus accumbens, is increased following repeated psychostimulant administration and that the activation of kappa opioid receptor systems can prevent these neurochemical effects. They have also shown that administration of either dynorphin, the endogenous ligand for the kappa opioid receptor, or synthetic kappa-opioid receptor agonists prevent relapse to cocaine addiction in experimental animals. These treatments also attenuate the enhanced behavioral responses to cocaine that develop in individuals with a prior history of cocaine administration. The administration of dynorphin-derived peptides is also effective in ameliorating the physical withdrawal syndrome that occurs following the cessation of repeated opiate use. These data indicate an important role of endogenous kappa-opioid receptor systems in opposing adaptations in behavior and brain function that occur in response to two classes of abused drugs and suggest that drugs that activate this system may be effective in the treatment of drug addiction.